Prognostic value of new left atrial volume index severity ...

Lazzeroni et al. Cardiovascular Ultrasound (2016) 14:35

DOI 10.1186/s12947-016-0077-0

RESEARCH

Open Access

Prognostic value of new left atrial volume

index severity partition cutoffs after cardiac

rehabilitation program in patients

undergoing cardiac surgery

Davide Lazzeroni1*, Nicola Gaibazzi2, Matteo Bini3, Giacomo Bussolati1, Umberto Camaiora1, Roberto Cassi1,

Simone Geroldi1, Pietro Tito Ugolotti1, Lorenzo Brambilla1, Valerio Brambilla1, Paolo Castiglioni4 and Paolo Coruzzi3

Abstract

Background: Previous studies showed that left atrial enlargement is an independent marker of adverse outcomes in

both primary and secondary cardiovascular prevention. However, no data are available on long-term outcomes in

patients undergoing valve surgery and/or coronary artery by-pass graft (CABG) surgery. Aim of the study was to

evaluate long-term prognostic role of left atrial volume index (LAVi) after cardiac surgery, using the cutoff values

recently proposed by the European Association of Cardiovascular Imaging and American Society of Echocardiography.

Methods: We created a retrospective registry of 1703 consecutive patients who underwent cardiovascular

rehabilitation program after cardiac surgery, including CABG, valve surgery and valve + CABG surgery. LAVi was

calculated as ratio of left atrium volume to body surface area, in ml/m2 at discharge; 563 patients with available LAVi

data were included in the study.

Results: In the whole population LAVi was 36 ¡À 14 ml/m2 (mean ¡À SD) and the follow-up time was 5 ¡À 1.

5 years. Increased LAVi (>34 ml/m2) predicted major adverse cardiovascular and cerebrovascular events

(MACCEs) (HR = 2.1; CI95 %: 1.4¨C3.1; p < 0.001) and cardiovascular mortality (HR = 2.2; CI95 %: 1.0¨C4.5; p = 0.032).

An increased LAVi remained MACCEs predictor after adjustement for age, gender, diabetes, atrial fibrillation at

discharge, echocardiographic E/A ratio and left ventricular ejection fraction (HR = 1.8; CI95 %: 1.0¨C3.0; p = 0.

036). When the study population was split according to increasing LAVi values, left atrium enlargement

resulted a predictor of progressively worse adverse outcome.

Conclusions: LAVi is a predictor of long-term adverse cardiovascular outcome after cardiac surgery, even after

correction for main clinical and echocardiographic variables. The recently recommended LAVi severity cutoffs

appear adequate to effectively stratify outcome in patients undergoing rehabilitation after cardiac surgery.

Keywords: Left atrial volume index, Coronary artery by-pass graft, Cardiac valve surgery, Echocardiography,

cardiovascular outcomes

Abbreviations: ACS, Acute coronary syndrome; CABG, Coronary artery by-pass graft; CRP, Cardiac

rehabilitation program; E/A, Ratio of the early to late ventricular filling velocities; EF, Ejection fraction;

HF, Heart failure; LA, Left atrium; LAVi, Left atrial volume index; LV, Left ventricle; MACCEs, Major adverse

cardiovascular and cerebrovascular events; MI, Myocardial infarction

* Correspondence: davide.lazzeroni@

1

Fondazione Don Carlo Gnocchi, University of Parma, Fondazione Don

Gnocchi, Piazzale dei servi n¡ã 3, 43121 Parma, Italy

Full list of author information is available at the end of the article

? 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0

International License (), which permits unrestricted use, distribution, and

reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to

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() applies to the data made available in this article, unless otherwise stated.

Lazzeroni et al. Cardiovascular Ultrasound (2016) 14:35

Background

Left atrium (LA) modulates left ventricular (LV) filling

and cardiovascular performance by functioning as a reservoir and a conduit for pulmonary venous return and as a

¡°booster¡± that augments ventricular filling during late ventricular diastole. LA also reflects LV filling pressure and is

capable of remodeling (enlarging) in response to its elevation [1, 2]. Although there is a growing body of evidence

demonstrating that LA enlargement is an independent

marker of adverse outcomes both in primary [3¨C7] and

secondary [8¨C11] cardiovascular prevention, to date, there

are no published data assessing long-term outcome in patients undergoing valve and coronary artery by-pass graft

(CABG) surgery.

Aim of this retrospective study was to examine longterm prognostic implications of left atrial volume index

(LAVi) assessment in patients undergoing cardiovascular

rehabilitation program (CRP) after cardiac surgery, using

the cutoff values proposed by the recently-published

guidelines of the European Association of Cardiovascular Imaging (EACVI) and American Society of Echocardiography (ASE) [12].

Methods

Patients¡¯ selection

We created a registry of consecutive patients undergoing

cardiovascular rehabilitation program (CRP) after cardiac

surgery, including CABG, valve surgery and combined

valve and CABG surgery, from January 2007 to June 2012.

A total of 1703 subjects (70 % men, mean age of 69 ¡À

11 years) were collected and, out of them, all 563 patients

with available biplane left atrial volume data were extracted

for the current analysis. The internal review board of Fondazione Don Gnocchi approved data collection. All patients completed a standard in-hospital CRP, lasting

approximately 2 weeks, consisting of supervised exercise

sessions (120 min per day), lifestyle and risk factor management, medical counseling and medical therapy

optimization. For each patient we collected variables from

medical record including anamnestic and demographic

findings, clinical and laboratory markers, electrocardiographic and echocardiographic measurements, physical

activity data, pharmacological therapy adherence. Outcomes were collected through a telephonic questionnaire

administered by a medical doctor or a supervised fellow

and all patients provided oral informed consent. End

points were: overall mortality and major adverse cardiovascular and cerebrovascular events (MACCEs) defined as either: cardiovascular (CV) mortality, non-fatal acute

coronary syndrome (ACS), heart failure (HF) and stroke.

Echocardiographic data

M-mode and 2-dimensional echocardiographic images

were obtained with a commercially available

Page 2 of 7

echocardiography machine (Esaote MyLab? 60). LA

volume was calculated using the biplane area-length

method at discharge of CRP [12]. Measurements were

obtained in end-systole from the frame preceding mitral valve opening. LAVi was calculated as the ratio of

LA volume to body surface area (ml/m2). In agreement with ASE and EACVI guidelines, we assumed

LAVi > 34 ml/m2 as the LA enlargement threshold

and we further classified LAVi values from 35 to

41 ml/ m2 as mild LA enlargement, from 42 to

48 ml/ m2 as moderate LA enlargement and greater

than 48 ml/ m2 as severe enlargement [12].

Statistical analysis

Continuous variables were expressed as mean (M) and

standard deviation (SD), categorical variables as number

(N) and percentage (%). The Student 2-sample t test,

Pearson ¦Ö2 test, Mann¨CWhitney¨CWilcoxon rank-sum

test were used to compare the differences between

groups for continuous, categorical and ordinal variables,

respectively. Cox proportional hazard regression analysis

was performed to create survival-free-from-event curves.

Multivariate Cox regression analysis was used to create

adjustment of hazard ratio (HR) for age, left ventricular

ejection fraction (LVEF), gender, diabetes, and ratio of

the early (E) to late (A) ventricular filling velocities (E/A

ratio). Event-free survival analysis was measured from

admission to the first event. Significance was defined as

a p value 34 ml/m2)

N = 306

N = 257

Age (years)

68 (10)

71 (9)**

Male sex

245 (61)

154 (39)**

BMI (kg/m2)

26.9 (4)

26.7 (4)

BSA (m2)

1.9 (0.2)

1.8 (0.2)**

CV risk Factors

Familiar history (CVD)

159 (56)

120 (44)

AHT

159 (52)

146 (48)

DM

83 (55)

66 (45)

Dyslipidaemia

165 (57)

120 (43)

197 (75)

95 (25)**

Types of cardiac surgery

CABG

Heart-valve surgery

73 (25)

118 (75)**

CABG + Valve surgery

37 (46)

43 (54)

ACS

116 (63)

68 (37)*

Stable Angina

66 (67)

32 (33)*

MV Stenosis

2 (22)

7 (78)

Clinical indications

MV regurgitation

44 (44)

56 (56)*

End point

AV Stenosis

23 (32)

20 (68)**

Mean follow-up was 5 ¡À 1.5 years. All-cause mortality

consisted in 55 deaths (10 %) and the total amount of

MACCEs was 114 (20 %), composed by 31 CV deaths

(5 %), 43 HF hospitalization (8 %), 15 strokes (3 %) and

25 ACS (4 %).

MACCEs were 2.1-fold higher in patients with LAVi >

34 ml/m2 compared with patients with normal LA volume, this difference being significant even considering

patients who received CABG or valve surgery separately

(in particular in patients with mitral and aortic regurgitation; see Table 2). Moreover, event-free survival from

MACCEs was significantly lower in both patients who

underwent CABG and valve surgery with enlarged LA

(Fig. 1).

By dividing the whole population according to severity partition cut-offs, MACCEs rate was significantly higher in patients with either moderate or

severe LA enlargement but not in those with mild

LA enlargement (Fig. 2 and Table 2). Multivariate

analysis, adjusted for age, gender, diabetes, E/A, atrial

fibrillation at discharge and LVEF, confirmed the role

of LA enlargement in predicting MACCEs in the

whole population; moreover, the progressive increase

of LAVi severity maintained an incremental risk of

MACCEs in patients with LA enlargement ranging

from moderate to severe (Fig. 3).

Severe LA enlargement resulted a significant and robust predictor of any type of secondary end point: all-

AV regurgitation

19 (46)

22 (54)

Other indication

36 (62)

22 (38)

LAV (ml)

49 (11)

85 (22)**

LAd (mm)

38 (5)

54 (6)**

LVEF (%)

52 (9)

49 (10)*

LV EDV (ml)

105 (41)

108 (42)

IVS (mm)

12 (2)

13 (2)**

E/A Ratio

1 (0.4)

1 (0.6)

Echocardiographic parameters

Medications

¦Â-Blocker

201 (52)

185 (48)

Amiodarone

79 (51)

77 (49)

OAT

72 (38)

117 (62)**

ACEi

216 (57)

170 (43)**

Statins

218 (56)

168 (44)**

Values are expressed as mean and standard deviation or as number

and percentage

LA left atrium; LAVi left atrial volume index; BMI body mass index; CVD

cardiovascular disease; AHT arterial hypertension; DM diabetes mellitus; CABG

coronary artery bypass graft; ACS acute coronary syndrome; MV mitral valve;

AV aortic valve; Lad left atrium antero-posteior diameter; LVEF left ventricular

ejection fraction; IVSs interventricular septum; LV EDV left ventricular enddiastolic volume; OAT oral anticoagulant therapy

*and **indicate differences at significance levels p 34 ml/m2. Event-free survival

from cardiovascular mortality was significantly lower

in these patients (Fig. 4), whilst only a trend towards

a higher all-cause mortality was found in patients

with LAVi > 34 ml/m2 (Table 2).

Discussion

The present study demonstrates, in a population of

563 patients followed for about 5 years after cardiac

surgery, that post-operative LAVi is a long-term predictor of MACCEs and CV mortality, also confirming

its prognostic value in predicting MACCEs even after

adjustment for age, gender, diabetes, atrial fibrillation

at discharge, E/A diastolic index and LVEF.

Left atrium reflects left ventricular filling pressure, a

parameter conditioned by structural and functional

heart impairement [1, 2]. Consequentely, LA enlargement is an echocardiographic marker that mirrors left

ventricular systolic and/or diastolic chronic dysfunction, representing a possible pathophysiological explanation of our results.

Previous studies in patients undergoing cardiac surgery only examined the relationship between LA volume and prevalence of either post-operative atrial

fibrillation [13] or symptomatic improvement of HF

Fig. 1 Left: LA enlargement and survival free from MACCEs in CABG patients. Right: LA enlargement and survival free from MACCEs in valve surgery

patients. MACCEs, major adverse cardiovascular and cerebrovascular events; LA, left atrium

Lazzeroni et al. Cardiovascular Ultrasound (2016) 14:35

Fig. 2 MACCEs and LA severity partition cut-offs after cardiac surgery.

MACCEs, major adverse cardiovascular and cerebrovascular events; LA,

left atrium

[14]. Therefore, our results offer novel data highlighting a

significant prognostic role of LAVi on MACCEs and CV

mortality in such patients. In addition, our study represents a convincing validation of the prognostic significance of the new severity partition cutoffs, suggested by

Fig. 3 Hazard Ratio with 95 % CI for MACCEs calculated after

adjustment for age, LVEF, gender, diabetes, atrial fibrillation at discharge

and E/A ratio, in subgroups of patients with mild, moderate and severe

LA enlargement, and in all patients with LA enlargement; * and **

indicate significant differences from HR = 1 at p < 0.05 and p < 0.01

significance levels

Page 5 of 7

both EACVI and ASE [12], in patients undergoing cardiac

surgery. In particular, we showed that moderate and severe LA enlargement is associated with increased rate of

MACCEs, while mildly increased LAVi represents a grey

zone which does not appear to robustly impact the

prognosis.

LA size is a recognized prognostic predictor in primary CV prevention. This was demonstrated in a 8year follow-up of 5209 individuals included in the

Framingham Heart Study, where an increased LA

diameter was associated with higher risk of stroke

and mortality [15] and other primary prevention studies suggested the independent role of LAVi in predicting CV death [3, 5, 7], MACCEs [5, 7], ischemic

stroke [6] and atrial fibrillation [4].

The prognostic significance of LAVi has been confirmed also in secondary CV prevention, especially in

patients after acute myocardial infarction (MI). An increased LA volume, assessed within the first 48 h of

admission, independently predicted 5-year mortality in

a population of 395 MI patients [8]. Similarly, LAVi

>32 ml/m2 did result an independent predictor of

mortality during a mean follow-up of 15 months in

314 MI patients [16], being these results thereafter

confirmed in a population of 610 subjects with highrisk MI followed for a mean of 20 months [9]. The

relationship between LAVi and CV outcomes was also

addressed in 935 outpatients with established coronary artery disease followed for about 4 years, concluding that

LAVi was similar to LVEF in predicting mortality and HF

hospitalization [17].

The prognostic implications of LA size were confirmed also in patients with valve disease, who did or

did not undergo cardiac surgery. Neverthless, the majority of these studies has been mainly focused on

post-operative atrial fibrillation [13, 18, 19], LVEF recovery [20] and HF symptoms [14], while harder endpoints, such as cardiovascular mortality, had only

been evaluated in 176 patients with symptomatic

chronic mitral regurgitation undergoing valve replacement by using pre-operative LA diameter [21].

Given that in previous studies the predictive significance of LA size was invariably investigated measuring LA diameter or LAVi with either arbitrary or

single cutoff value, our study could represent the first

prognostic validation of the new three cutoffs of severity partition, recently recommended by both

EACVI and ASE. Our results highlight the importance to quantify the LA size in terms of LAVi; they

also suggest that LAVi should be measured not only

in routine clinical practice but also in a rehabilitation

setting for more accurate risk-stratification and

clinical decision making in patients who underwent

cardiac surgery.

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